1. Field of the Invention
This invention relates to an additional medical use of thiazolidinediones, some of which are used in the treatment of diabetes and essential hypertension. These compounds are also useful for the treatment of psoriasis.
2. Background
Psoriasis is a disease which afflicts primarily the skin and produces raised, thickened, scaling, non-scarring lesions. The lesions are usually sharply demarcated erythematous papules covered with overlapping shiny scales. The scales are typically silvery or slightly opalescent. Involvement of the nails frequently occurs resulting in pitting, separation of the nail, thickening and discoloration. Arthritis is sometimes associated with psoriasis, and it may be crippling. Psoriasis afflicts about 1-2% of the United States population with about 200,000 new cases diagnosed annually. Some estimate that there are up to five million patients with psoriasis in the United States.
Hyperproliferation of keratinocytes is a key feature of psoriasis along with epidermal inflammation and reduced differentiation of keratinocytes. Multiple mechanisms have been invoked to explain the keratinocyte hyperproliferation that characterizes psoriasis. However, no single mechanism has been definitively implicated. Activation of epidermal growth factor receptors, alterations in protein kinase C signal transduction pathways, and the attendant changes in intracellular calcium metabolism may play a role in psoriatic epidermal hyperplasia. Disordered cellular immunity has also been implicated in the pathogenesis of psoriasis. However, the exact mechanisms of keratinocyte hyperproliferation and epidermal inflammation remain unclear.
Because of the multifactorial nature of psoriasis, it is difficult to predict whether pharmacologic manipulation of complex signal transduction pathways, growth factor receptors, or cellular immune functions will attenuate the hyperproliferation of keratinocytes. A number of diverse pharmacologic therapies have been tried with varying degrees of success. Current treatments of psoriasis include tar based therapies, psoralens with ultraviolet light, immunosuppressants such as cyclosporine and methotrexate, glucocorticoids, retinoids, and vitamin D analogs.
Although the current therapies for psoriasis share the common feature of inhibiting hyperproliferation of keratinocytes, they act through different cellular mechanisms and are accompanied by a variety of side effects that are at best unpleasant and often dangerous. For instance, tar based therapies are uncomfortable and a nuisance to apply. Immunosuppressants like methotrexate can predispose to malignancy, cyclosporine can cause renal damage and hypertension, glucocorticoids can cause local and serious systemic side effects such as adrenal suppression, vitamin D analogs can cause disordered calcium metabolism, and retinoids can have a broad range of side effects and are teratogens. Because of the distressing and disfiguring nature of psoriasis and the unsatisfactory aspects of current therapies, there is considerable interest in developing alternative therapeutic approaches to treating this hyperproliferative skin disorder.